title: Synovial fibroblasts directly induce Th17 pathogenicity via the cyclooxygenase/prostaglandin E2 pathway, independent of IL-23.
abstract: Th17 cells are critically involved in autoimmune disease induction and severity. Recently, we showed that Th17 cells from patients with rheumatoid arthritis (RA) directly induced a proinflammatory loop upon interaction with RA synovial fibroblasts (RASF), including increased autocrine IL-17A production. To unravel the mechanism driving this IL-17A production, we obtained primary CD4(+)CD45RO(+)CCR6(+) (Th17) cells and CD4(+)CD45RO(+)CCR6(-) (CCR6(-)) T cells from RA patients or healthy individuals and cocultured these with RASF. IL-1β, IL-6, IL-23p19, and cyclooxygenase (COX)-2 expression and PGE2 production in Th17-RASF cultures were higher than in CCR6(-) T cell-RASF cultures. Cytokine neutralization showed that IL-1β and IL-6, but not IL-23, contributed to autocrine IL-17A induction. Importantly, treatment with celecoxib, a COX-2 inhibitor, resulted in significantly lower PGE2 and IL-17A, but not IFN-γ, production. Combined celecoxib and TNF-α blockade more effectively suppressed the proinflammatory loop than did single treatment, as shown by lower IL-6, IL-8, matrix metalloproteinase-1 and matrix metalloproteinase-3 production. These findings show a critical role for the COX-2/PGE2 pathway in driving Th17-mediated synovial inflammation in an IL-23- and monocyte-independent manner. Therefore, it would be important to control PGE2 in chronic inflammation in RA and potentially other Th17-mediated autoimmune disorders.
authors.affiliation: Department of Rheumatology, Erasmus University Medical Center, Erasmus University, 3000 DR Rotterdam, The Netherlands.
authors.forename: Sandra M J
authors.initials: SM
authors.lastname: Paulissen
authors.forename: Jan Piet
authors.initials: JP
authors.lastname: van Hamburg
authors.forename: Nadine
authors.initials: N
authors.lastname: Davelaar
authors.forename: Patrick S
authors.initials: PS
authors.lastname: Asmawidjaja
authors.forename: Johanna M W
authors.initials: JM
authors.lastname: Hazes
authors.forename: Erik
authors.initials: E
authors.lastname: Lubberts
mesh_terms: D001172:Arthritis, Rheumatoid / Q000276:immunology / Q000378:metabolism*; D015704:CD4 Antigens / Q000378:metabolism; D000068579:Celecoxib; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000378:metabolism*; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D007371:Interferon-gamma / Q000096:biosynthesis; D020381:Interleukin-17 / Q000096:biosynthesis; D053583:Interleukin-1beta / Q000096:biosynthesis; D053760:Interleukin-23 Subunit p19 / Q000096:biosynthesis / Q000378:metabolism; D015850:Interleukin-6 / Q000096:biosynthesis; D016209:Interleukin-8 / Q000096:biosynthesis; D017493:Leukocyte Common Antigens / Q000378:metabolism; D008297:Male; D020781:Matrix Metalloproteinase 1 / Q000096:biosynthesis; D019278:Matrix Metalloproteinase 3 / Q000096:biosynthesis; D008875:Middle Aged; D011720:Pyrazoles / Q000494:pharmacology; D054399:Receptors, CCR6 / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology; D013583:Synovial Membrane / Q000166:cytology / Q000378:metabolism; D058504:Th17 Cells / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors
chemical_list: C106311:CCR6 protein, human; D015704:CD4 Antigens; D052246:Cyclooxygenase 2 Inhibitors; C508717:IL17A protein, human; D020381:Interleukin-17; D053583:Interleukin-1beta; D053760:Interleukin-23 Subunit p19; D015850:Interleukin-6; D016209:Interleukin-8; D011720:Pyrazoles; D054399:Receptors, CCR6; D013449:Sulfonamides; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D017493:Leukocyte Common Antigens; D019278:Matrix Metalloproteinase 3; D020781:Matrix Metalloproteinase 1; D000068579:Celecoxib; D015232:Dinoprostone